Regulatory Decision Summary for Xeljanz

Psoriatic Arthritis (PsA) is a chronic progressive inflammatory arthritis that may result in permanent joint damage, disability and adverse effects on quality of life, which include fatigue and impairment in physical function. There is currently no cure for PsA. The current goals of therapy for patients with PsA are to treat the symptoms, minimize damage, and improve quality of life. Common treatments include conventional synthetic disease-modifying anti-rheumatic drug (csDMARD) and biologic DMARD (bDMARD), both of which have limitations. Currently, there are few options for patients who have inadequate response to one or more csDMARD and in whom bDMARD are not appropriate, and patients who have an inadequate response to tumor necrosis factor inhibitor (TNFi-IR).

The efficacy of tofacitinib (5 mg BID and 10 mg BID) is supported by two Phase 3 pivotal clinical studies and one Phase 3 long-term extension study. All subjects remained on a stable dose of single background csDMARD (predominantly methotrexate). Both tofacitinib doses showed statistically and clinically significant improvements over placebo for the treatment of the arthritic component of PsA at Month 3 in csDMARD-IR/TNFi-naïve patients and TNFi-IR patients (primary endpoints: ≥20% improvement in the American College of Rheumatology responder rates [ACR20] and change in Health Assessment Questionnaire - Disability Index [∆HAQ-DI]). Adalimumab (TNFi) was used as an active control in csDMARD-IR/TNFi-naïve patients. The efficacy of tofacitinib dosed at either 5 mg BID or 10 mg BID was comparable to that of adalimumab. Tofacitinib also showed nominal or numerical improvements over placebo for the treatment of the psoriasis, enthesitis, and dactylitis components of PsA in both populations at Month 3. Although the placebo comparator was no longer available beyond Month 3, the efficacy was sustained up to 12 months in csDMARD-IR/TNFi-naïve patients and up to 6 months in TNFi-IR patients. In a long-term extension study, the efficacy was further sustained for an additional 15 months. The radiographic response treatment effect cannot be established but shows promising results. Differences in efficacy between the 5 mg BID and 10 mg BID doses at most endpoints were not consistent or clinically significant.

The safety of tofacitinib is supported by 783 PsA subjects, the majority of which were evaluated up to 36 months at the time of data-lock. Due to a relatively small supplemental development program for PsA and the observation that the safety profiles between PsA and rheumatoid arthritis (RA) patients were very similar, the safety of tofacitinib is also supported by 6300 RA subjects, evaluated for more than 42 months.

PsA and RA patients treated with tofacitinib have identified risks for increased serious infections, herpes zoster, opportunistic infections, and non-melanoma skin cancer (NMSC). Other important potential risks of tofacitinib in the PsA and RA populations include cardiovascular events (including major cardiovascular events), malignancies (excluding NMSC), gastrointestinal perforation, and drug-induced liver injury (DILI). PsA and RA patients treated with tofacitinib may also have an increased risk of developing anemia, neutropenia, and lymphopenia.

Due to the fact that there is a higher risk of developing infections and anemia at the 10 mg BID dose compared to the 5 mg BID dose, and that there is only an incremental increase in efficacy, the recommended dose for tofacitinib to treat PsA is 5 mg BID.

The observed safety findings in the PsA program were consistent with those observed in both short and long-term data from the RA development program. No new safety risks were identified for PsA subjects. Risks associated with treatment can be mitigated by adapting the existing measures employed for the approved indication of RA. Consistent with the requirements for RA, tofacitinib should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of PsA.

Tofacitinib 5 mg BID showed consistent and sustained improvements in both physician-assessed and patient-reported efficacy measures for the PsA disease domain of peripheral arthritis; improvements in the domains of psoriasis, enthesitis, and dactylitis have also been observed. The safety profile of tofacitinib 5 mg BID in the PsA development program is consistent with that observed in the tofacitinib RA development program, which has been shown to be manageable with the current Risk Management Plan (RMP). The same routine risk minimisation information in the PM for RA is being conveyed as routine risk minimisation for PsA. The additional risk minimization measures in the form of educational material for healthcare professionals and patients are intended to inform on risks included in the label. Tofacitinib 5 mg BID has a favourable benefit-risk ratio for the treatment of PsA in csDMARD-IR/TNFi-naïve patients and TNFi-IR patients. In addition, the oral administration of tofacitinib will offer more convenience and likely greater compliance in patients with PsA over bDMARDs which requires parenteral administration. Tofacitinib 5 mg BID is recommended for approval for the PsA indication.